Lung cancer is the leading cause of cancer mortality for both men and women in the US. Current cytotoxic chemotherapy for lung cancer lacks specificity and efficacy, which provides an impetus to develop targeted therapies to achieve greater efficacy with fewer side effects. The long-term goal of this application is to develop polymeric micelles as an enabling nanomedicine platform to achieve targeted therapy for lung cancer. Hydrophobic drugs will be loaded inside the micelle cores to overcome limitations of low water solubility and poor pharmacokinetics. Recently, we demonstrated that micelles encoding surface functionalized cyclic Arg-Gly-Asp (cRGD) peptide have dramatically increased (>30 fold) uptake in alpha(v)beta(3) integrin-overexpressing tumor endothelial cells and subsequently resulted in efficient targeting to solid tumors in vivo. In this application, we will apply the micelle technology to incorporate a novel class of lung cancer targeting peptides identified from phage screening for specific drug targeting to lung cancer cells. The isolated peptides have demonstrated remarkable binding affinities (<nM) and cell specificities (20-1000 fold) to discriminate between different cell types. Our central hypothesis is that lung cancer peptide (LCP)-encoded micelles will provide a safe and efficacious therapeutic system for targeted therapy of lung cancer. To test this hypothesis, we will carry out the following three Specific Aims: (1) Develop LCP-encoded micelles and evaluate their affinity and specificity to different lung cancer cells in vitro. (2) Evaluate the pharmacokinetics and intratumoral distribution of LCP-encoded micelles in vivo. (3) Validate the therapeutic efficacy of LCP-encoded micelles in mice bearing orthotopic human lung xenografts in vivo. If successfully established, these micelles will provide a powerful nanomedicine platform that will impact the translation of novel molecular targets of lung cancer in clinical therapy.